Sturge-Weber Syndrome (SWS) is a skin, eye, and brain vascular disorder of capillary angiomas resulting in port wine stain angiomas affecting the skin, angiomas and glaucoma of the eye, and leptomeningeal angiomas surrounding the brain. In 2013, members of the Brain Vascular Malformations Consortium (BVMC) co-identified a somatic, activating mutation in the GNAQ gene (which encodes the G alpha subunit) in affected vascular tissue. This mutation occurs during fetal development and thus, even with early diagnosis, the vascular malformation is already present and may not be reversible. However, as with many vascular brain lesions, serious complications can arise from the effects of the vascular malformation and the surrounding brain parenchyma. Recently, the Sturge-Weber Foundation (SWF) brought together patients and clinicians to identify unmet needs for patients. While neurological symptoms including seizures and headaches are common, stroke-like episodes, severe bouts of seizures, and migraine headaches were felt to significantly impact patient quality of life. Current treatments used to prevent these symptoms include aspirin and seizure medications, but neither is well supported by longitudinal studies. Nor is it clear exactly what causes stroke-like symptoms or how to identify SWS patients at risk for these symptoms. Elegant serial brain imaging studies from our previous grant period have provided important clues showing changes in the vascular structures themselves as well as surrounding brain parenchyma, including dense brain calcifications that could underlie these symptoms. Hence, another potentially exciting treatment is to target brain calcifications through a repurposed drug. Here, we will address pressing needs for clinical trial readiness through the identification of at risk patients, analysis of current treatments, and identification of robust, clinically useful and predictive biomarkers. We plan to extend our patient registry data to integrate longitudinal clinical, radiological, and blood biomarkers of patients to identify those at most risk to have severe neurological symptoms and to identify potential treatments (Aim 1). We will identify imaging biomarkers that will change over time and correlate with severe neurological symptoms (Aim 2). Finally, for enrolled patients who present with severe neurological symptoms, plasma samples will be screened for inflammatory changes at baseline, during, and after the severe symptoms to identify predictive biomarkers for clinical trials (Aim 3). A major deliverable will be a clinically useful, integrated longitudinal database and dashboard tool to help visualize data that will help clinicians better understand progression of disease course following the SWS mutation.